Anti-analgesia of a selective NPFF2 agonist depends on opioid activity

NPFF agonists designed to be selective NPFF2 receptor probes were synthesized. D.Asn-Pro-(N-Me)Ala-Phe-Leu-Phe-Gln-ProGln-Arg-Phe-NH2 (dNPA) displays a very high affinity (0.027 nM) for NPFF2 receptors transfected in CHO cells, and a very high selectivity with a discrimination ratio greater than 100 versus NPFF1 receptors. dNPA acts as a potent and selective agonist in [S-35]GTP gamma S binding experiments and inhibits intracellular cAMP production with the same efficacy as NPA-NPFF. In SH-SY5Y cells expressing NPFF2 receptors dNPA, in the presence of carbachol, stimulates Ca2+ release from the intracellular stores. In vivo, after intracerebroventricular injection dNPA increases body temperature in mice and reverses the morphine-induced analgesia. Also, dNPA displays anti-opioid activity after systemic administration. So far, dNPA exhibits the highest affinity and selectivity for NPFF2 receptors and reveals that its behavioral anti-opioid activity depends on the degree of opioid-induced analgesia. (c) 2005 Elsevier Inc. All rights reserved.